JPH04297437A - New alpha-hydroxyl acid and method of manufacturing same - Google Patents

Abstract

PURPOSE: To provide novel α-hydroxylated β-unsatd. carboxylic acids useful as intermediates capable of predicting homologous lower aldehydes, more particularly prenal and citral in a very good yield.

CONSTITUTION: The compd. of formula I ((n) is 0, 1, 2, 3); for example, 2- hydroxy-4-methyl-pente-3-hydrochloric acid. This compd. may be produced by i) specification of the compd. of formula II (R is a 1 to 4C alkyl) to form the corresponding acid, ii) then converting this acid to dianion by the effect of the base selected from among an alkaline metal hydride which may be deposing or grafted to a carrier or amides and org. metal alkyls in an org. solvent and iii) further oxidizing the same. The homologous lower aldehydes useful as the intermediates for vitamin A or arom. agents can be produced if the compd. of the formula I is oxidatively decarboxylated.

COPYRIGHT: (C)1992,JPO

Description

[Detailed description of the invention]

The present invention relates to novel α-hydroxylated β-unsaturated carboxylic acids. More specifically, the invention relates to the general formula:

0002

[Chemical formula 3]

The present invention relates to novel α-hydroxy-acids, processes for their preparation and uses thereof. In particular, these novel products can be synthesized from homologous lower aldehydes (prenal, citral, etc.) by oxidative decarboxylation.
・) is an intermediate product that can be produced. Such aldehydes can produce vitamin A,
Or they can be used because of their aromatic properties.

The preparation of α-ethylene carbonyl compounds by isomerization of α-acetylenic alcohols is known from French patent 1,554,805. This isomerization is optionally carried out in a solvent by 3b-7 of the Periodic Table of the Elements.
It is carried out by heating the alcohol in the presence of a small amount of a catalyst based on a metal belonging to group b. Advantageously, this isomerization is carried out in the liquid phase and the catalyst is an inorganic or organic derivative of a metal selected from the group consisting of vanadium, niobium, molybdenum, tungsten and rhenium.

Unsaturated aldehydes are prepared from 1,1-disubstituted propargyl alcohols by heating in an acidic medium in the presence of a catalyst containing a metal belonging to group 1b of the Periodic Table of the Elements. Also, US Patent 3,0
57,888. Furthermore, it is also known from US Pat. Nos. 2,524,865 and 2,524,866 to prepare ethylenic aldehydes by treating alkynols in the gas phase with the action of various acidic catalysts. However, this process gives only ternary mixtures of ethylenic aldehydes, ketones and hydrocarbons.

The present invention describes a new process for the preparation of these aldehydes, in particular prenal and citral, from esters of β,γ-unsaturated carboxylic acids. Furthermore, this process gives very good yields and makes it possible to provide and isolate new α-hydroxylated β-unsaturated carboxylic acid compounds as intermediate products.

[0007] Therefore, one object of the present invention is to provide the general formula (I)

[
0008

[C4]

[0009] It relates to novel compounds in which n can be 0, 1, 2 or 3.

In particular, the present invention provides general formula (I) in which n=0
2-hydroxy-4-methyl-pent-3-enoic acid and n=1, 2-hydroxy-4,8-dimethyl-nona-3,7-dienoic acid.

Another subject of the invention is that in a first step the general formula:

0012

[C5]

The ester of R is an alkyl group having 1-4 carbon atoms and n is 0, 1, 2 or 3 is saponified to form the corresponding acid, and the second obtained in this way by the action of a base selected from alkali metal hydrides or amides and organometallic alkyls, optionally deposited or grafted onto a support, in an organic solvent. to produce acid dianion,
And in the third step, the dianion is oxygenated to give formula (I)
Following the process of producing acids, these compounds can be expressed by the general formula (
The present invention relates to a method of manufacturing from esters of β,γ-unsaturated carboxylic acids as described in II).

More specifically, the first step of this process is to prepare an ester (I) for producing an acid of general formula (III) below.
I) includes the saponification reaction:

[0015]

[C6]

In a particular embodiment of the invention, R, which may be an alkyl group preferably having 1 to 4 carbon atoms, is a methyl group, and n, which may be 0, 1, 2 or 3, is 0 (4 −
methyl-pent-3-enoate) or 1 (
4,8-dimethyl-nona-3,7-dienoate).

The saponification reaction can be carried out in an organic solvent using a strong base of the M--OH type (where M is preferably an alkali metal or a quaternary ammonium group). In particular, this can be carried out in water-miscible solvents such as, for example, alcohols (methanol, ethanol, isopropanol...). In certain embodiments of the invention, methanolic sodium hydroxide is used.

The reaction temperature is preferably between ambient temperature and the reflux temperature of the mixture.

Esters of general formula (II) can be prepared from isoprene or higher homologs according to the method described in French patent FR 81 01,205. The reaction is as follows:

[0020]

[C7]

This carbonylation reaction is carried out using carbon monoxide, an alcohol corresponding to the desired ester, a hydrohalic acid (especially hydrochloric acid or hydrobromic acid), and a palladium catalyst (palladium metal, palladium oxide, palladium salt, Or, the anion coordinating with the palladium cation is “hard” or “intermediate”.
at a temperature between 50-150° C. and at a temperature of 50-300 bar. Performed under carbon oxide pressure. Under these conditions esters are obtained in very good yields.

Regarding the second step of the process, ie the preparation of the dianion of acid (III), the following steps can be carried out: The dianion may optionally be deposited or grafted onto a support, for example They are obtained in organic solvents by the action of alkali metal hydrides or bases such as amines or organometallic alkyls. According to the invention, the alkali metal amide can be selected from lithium diisopropylamide (LDA), sodium tert-butyrate or sodium amide, which can be prepared in situ by the action of butyllithium on diisopropylamine. Hydrides that can be used in this reaction include sodium, potassium or calcium hydrides. Regarding organometallic alkyls, organolithium compounds, organomagnesium compounds, and sodium or potassium alkyls can be used. Particular mention may be made of butyllithium.

In a preferred embodiment of the invention, LDA is used as the base.

In the case of heterogeneous bases, it is possible in particular to use supports of the oxide type, such as in particular aluminas. In this connection, potassium tert-butyrate and potassium fluoride on alumina may be mentioned as heterogeneous bases.

As regards organic solvents, all ether type solvents are suitable for this reaction. Preference is given to using tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether or paradioxane. In a preferred embodiment, tetrahydrofuran is used.

Finally, the reaction forming the dianion is advantageously carried out at low temperatures and in particular at temperatures between -20°C and +20°C, preferably between -10°C and +10°C. In some cases, the temperature can be temporarily raised at the end of the reaction in order to shift the equilibrium of the reaction as much as possible towards the dianion. This heat finishing treatment is carried out at a temperature between 20°C and 50°C and preferably between 30°C and 40°C.

The third step regarding the oxygenation of the dianion is preferably carried out in the following manner: The oxygenation of the dianion to produce the α-hydroxy-acid of general formula (I) is carried out by:
It is carried out using oxygen or air optionally enriched with oxygen, and preferably air. It can be carried out by contacting oxygen or air with a stirred solution of the dianion or by flowing it over the surface of the solution. In another embodiment, oxygenation can be performed using compressed air. Advantageously, this reaction is carried out after the temperature has reached a value near ambient temperature.

When carrying out the process that is the subject of the invention, by-products may also be formed, in which case the oxygenation of the acid
- It didn't happen in that position. However, these products occur only in very small quantities and, due to their low crystallinity, can be removed by filtration after crystallization of the main product.

Another subject of the invention is the use of these new compounds for preparing homologous lower aldehydes by oxidative decarboxylation using oxidizing agents. The reaction formula is as follows:

[0030]

[Chemical formula 8]

[0031] This reaction can be carried out using, for example, cobalt, manganese,
It can be carried out using oxidizing agents such as acetates of one or more metals selected from lead, silver or the copper-lead pair and preferably from cobalt and lead. In particular, lead tetraacetate gives very good results. Oxidative decarboxylation was described by Maumy et al. (Tetrahedron Le
It is likewise possible to carry out indirectly by free radical techniques. In particular, metals, such as in particular Cu2O, can be used at atmospheric pressure in solvents that stabilize copper(I), such as, for example, acetonitrile.

Other objects and advantages of the invention will be understood from a reading of the following examples, which are to be considered illustrative and not non-limiting.

[0033]

EXAMPLES Example 1 Synthesis of 4-methyl-pent-3-enoic acid by saponification of methyl 4-methyl-pent-3-enoic acid 12.8 g (100 mmol) of the ester was used, and 50 ml of the ester was used. Diluted with methanol. 15ml of 30
% sodium hydroxide solution (112 mmol) was added dropwise. The resulting solution was heated under reflux for 3 hours with stirring. The solvent was then evaporated to dryness and the remaining carboxylate was treated with 15 ml of concentrated HCl. The acid was then extracted with ether and the extract was dried over Na2SO4. The ether was then evaporated and remaining traces of water were removed under a vane-pump vacuum. Under these conditions, the ester conversion was 100% and the yield was 92%.

Example 2 Preparation of 2-Hydroxy-4-methyl-pent-3-enoic acid A solution of 4 g of diisopropylamine in 60 cm3 of anhydrous tetrahydrofuran was added under an argon atmosphere to a central stirrer, a condenser, a 50 cm3 dropping funnel, and a gas inlet. and into a three-necked 250 cm3 reactor equipped with a heating system. The reactor was cooled with an ice bath and then 37 cm3 of a 1.1 molar (M) solution of butyllithium in hexane was added dropwise, keeping the temperature below 5°C. After stirring for 30 minutes at a temperature of 2°C, 2.28 g
of 4-methyl-pent-3-enoic acid in 30 cm3 of anhydrous tetrahydrofuran was added. After stirring for 30 minutes, the reaction mixture was heated at 40° C. for 1 hour.

After cooling to a temperature around 20° C., air was added using a balloon over a period of 3 hours, with constant vigorous stirring. After the reaction, the acid was measured by proton nuclear magnetic resonance at 360 MHz.

After the reaction had ended, 250 cm 3 of water were added twice.

The aqueous phase which was decanted and separated was concentrated, then acidified using concentrated hydrochloric acid and finally extracted with ether.

After drying and concentrating the ether phase an oil was obtained which slowly crystallized on cooling.

The crude product obtained contains 90% 2-hydroxy-4-methyl-pent-3-enoic acid and 10%
of 4-hydroxy-4-methyl-pent-3-enoic acid.

2-Hydroxy-4-methyl-pente-3
- Enoic acid was separated by filtration on fritted glass.

2-Hydroxy-4-methyl-pente-3
- Enoic acid had the following physicochemical properties: - Melting point: 95-98°C - Elemental analysis: C% Calculated value: 55.37 Actual value:
54.76 H% calculated value:
7.75 Actual value: 7.28 - Infrared spectrum (tablets mixed with KBr): Characteristic band: 3400c
m-1 (alcoholic OH), 3100-2300cm
-1 (acidic OH), 2980 cm-1 (CH3), 17
05 cm-1 (C=O, acid) and 1070 cm-1 (
C-O, alcohol) -proton nuclear magnetic resonance spectrum (360MHz, CD
Cl3, chemical shift with respect to hexamethyldisilane taken as reference, ppm): 5.13 (d, 1H
, =CH-); 4.85(d, 1H, =CH-CH(O
H)-; 1.72 (2s, 6H, 2xCH3)-Mass spectrum (m/e): M+ = 130.

The conversion rate of 4-methyl-pent-3-enoic acid was 58%.

Example 3 The process of Example 2 was repeated, but with air flowing over the surface.

The conversion rate of 4-methyl-pent-3-enoic acid was 100%.

2-Hydroxy-4-methyl-pente-3
- Enoic acid was isolated with a yield of 87%.

4-Hydroxy-4-methyl-pente-3
- Enoic acid was isolated with a yield of 5%.

Example 4 Preparation of prenal from α-hydroxy-acid 0.143 g of 2-hydroxy-4-methyl-pentene
3-enoic acid, 5 cm3 of an aqueous solution containing 90% acetic acid and 0.54 g lead tetraacetate were added into a 50 cm3 flask equipped with a magnetic stirrer. The mixture was stirred at 25°C for 1 hour. 0.35 moles (M
) Sulfuric acid was added and the precipitated lead sulfate was separated by filtration. Prenal was quantitatively precipitated in the filtrate in the form of 2,4-dinitro-phenylhydrazone.

The yield was 70.3%.

Example 5 0.143 g of 2-hydroxy-4-methyl-pent-3-enoic acid, 5 cm3 of 1,2-dichlorobenzene and a small amount of 0.54 g of lead tetraacetate were added to a reactor equipped with a magnetic stirrer. The mixture was added to a 50 cm3 flask. The mixture was stirred at 25°C for 1 hour. After decanting, analysis of the reaction mixture by gas chromatography revealed a conversion of 2-hydroxy-4-methyl-pent-3-enoic acid of 100%.
% and the yield of prenal was shown to be 86%.

The main features and aspects of the present invention are as follows.

1. General formula:

[0052]

[Chemical formula 9]

[In the formula, n is 0, 1, 2 or 3]
compound.

2. The compound of 1 above, wherein n=0.

3. Compound 2 above, which is 2-hydroxy-4-methyl-pent-3-enoic acid.

4. In the first step, the general formula:

[0057]

[Chemical formula 10]

The ester of R is an alkyl group having 1 to 4 carbon atoms and n is 0, 1, 2 or 3 is saponified to form the corresponding acid, and the second obtained in this way by the action of a base selected from alkali metal hydrides or amides and organometallic alkyls, optionally deposited or grafted onto a support, in an organic solvent. to produce acid dianion,
And in the third step, the dianion is oxygenated to give formula (I)
4. A method for producing a compound according to any one of 1-3 above, which comprises producing an acid.

5. 4. Process according to claim 4, wherein the saponification is carried out using a strong base of the formula M-OH, where M is an alkali metal or a quaternary ammonium group.

6. The method of 5 above, wherein saponification is carried out using methanolic sodium hydroxide.

7. Alkali metal amides include lithium diisopropylamide (LDA), sodium tert.
butyrate or sodium amide, 4 and 5 above.
Or method 6.

8. the alkali metal amide is LDA,
Method 7 above.

9. The method of 4, 5 or 6 above, wherein the organometallic alkyl is an organolithium compound, an organomagnesium compound, or a sodium or potassium alkyl.

10. 4 and 5 above, wherein the hydride is sodium hydride, potassium hydride or calcium hydride
Or method 6.

11. 10. The method of any of 4-9 above, wherein the base is deposited or grafted onto an oxide-type support.

12. 4-1 above, where the solvent is ether
Either method 1.

13. The ether is tetrahydrofuran (T
HF), diisopropyl ether, methyl tert-butyl ether or paradioxane,
Method 2.

14. 13 above, wherein the organic solvent is THF
the method of.

15. 15. The method of any of 4-14 above, wherein the dianion is oxygenated using oxygen or air optionally enriched with oxygen.

16. 15 above methods using air.

17. The method of 4-16 above, wherein the dianion is produced at a temperature between -20°C and +20°C.

18. 17. The method of 17 above, wherein the temperature is between -10°C and +10°C.

19. In general formula (II), R is a methyl group, n=0, and the generated acid is 2-hydroxy-4-methyl-pent-3-enoic acid, any one of the above 4-17 Method.

20. A method for producing homologous lower aldehydes, which comprises oxidative decarboxylation using an oxidizing agent comprising a compound according to any one of 1-3 above.

21. 20. The method of 20 above, wherein the oxidizing agent is an acetate of one or more metals selected from cobalt, manganese, lead, silver, or the copper-lead pair.

22. 22. The method of 21 above, wherein the acetate is cobalt or lead.

Claims (3)

[Claims] [Claim 1] General formula: [Chemical formula 1] A compound of the formula: wherein n is 0, 1, 2 or 3. 2. In the first step, an ester of the general formula: [Image Omitted] wherein R is an alkyl group having 1 to 4 carbon atoms, and n is 0, 1, 2 or 3; is saponified to form the corresponding acid, in a second step from alkali metal hydrides or amides and organometallic alkyls, optionally deposited or grafted onto a support, in an organic solvent. 1 . The method of claim 1 , comprising producing a dianion of the acid thus obtained by the action of a selected base and, in a third step, oxygenating the dianion to produce the acid of formula (I). Methods for producing the described compounds. 3. oxidative decarboxylation using an oxidizing agent comprising the compound according to claim 1,
A method for producing homologous lower aldehydes.